Abstract
Non-alcoholic steatohepatitis (NASH) is a severe, advanced form of non-alcoholic fatty liver disease (NAFLD) that is associated with features of metabolic syndrome and characterized by hepatic steatosis, inflammation, and fibrosis. In addition, NASH is associated with endothelial dysfunction within the hepatic vasculature. Treatment with CU06-1004 (previously called Sac-1004) ameliorates endothelial dysfunction by inhibiting hyperpermeability and inflammation. In this study, we investigated the protective effects of CU06-1004 in a choline-deficient L-amino acid (CDAA)-induced mouse model of NASH for 3 or 6 weeks. Specifically, we evaluated the effects of CU06-1004 on lipid accumulation, inflammation, hepatic fibrosis, and liver sinusoidal endothelial cell (LSEC) capillarization through biochemical analysis, immunohistochemistry, and real-time PCR. We found that the administration of CU06-1004 to mice improved liver triglyceride (TG) and serum alanine aminotransferase (ALT) in this CDAA-induced model of NASH for 6 weeks. In groups of NASH induced mice for both 3 and 6 weeks, CU06-1004 significantly reduced the hepatic expression of genes related to lipogenesis, inflammation, and cell adhesion. However, expression of genes related to hepatic fibrosis and vascular endothelial changes were only decreased in animals with mild NASH. These results suggest that the administration of CU06-1004 suppresses hepatic steatosis, inflammation, fibrosis, and LSEC capillarization in a CDAA-induced mouse model of NASH. This suggests that CU06-1004 has therapeutic potential for the treatment of mild NASH.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a broad term covering a range of chronic liver diseases and is a major cause of conditions related to metabolic syndrome, including obesity, type 2 diabetes, and insulin resistance [1]
The body weight of both groups of mice was increased after a cholinedeficient L-amino acid (CDAA) diet for 3 or 6 weeks relative to control animals, but there was no significant difference in body weight between the mild or moderate Non-alcoholic steatohepatitis (NASH) groups (S1 Fig, Fig 1B)
We investigated the therapeutic potential of CU06-1004 in a CDAA-induced mouse model of NASH
Summary
Non-alcoholic fatty liver disease (NAFLD) is a broad term covering a range of chronic liver diseases and is a major cause of conditions related to metabolic syndrome, including obesity, type 2 diabetes, and insulin resistance [1]. Several studies have tested various treatment approaches for NASH, there is no approved, effective therapy available to date [3,4,5].
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